Comparisons of side effects using air and carbon dioxide foam for endovenous chemical ablation

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1 Comparisons of side effects using air and carbon dioxide foam for endovenous chemical ablation Nick Morrison, MD, a b a Diana L. Neuhardt, RVT, Charles R. Rogers, MD, James McEown, MD, a a a Terri Morrison, RN, BSED, Elaine Johnson, RN, BSN, CNOR, and b Sergio X. Salles-Cunha, PhD, Scottsdale, Ariz Objective: This clinical study evaluated prospectively adverse events immediately following ultrasound-guided foam sclerotherapy (UGFS) for the treatment of lower extremity venous valvular insufficiency. Incidence of side effects associated with carbon dioxide (CO 2 ) foam was compared with a historical control using air-based foam. The literature on the subject was reviewed. Methods: Vital signs were monitored during and immediately after UGFS, and adverse events were recorded for 24 hours following the procedure. The air-based foam group had 49 patients: 44 women and 5 men. 2-based The COfoam group had 128 patients: 115 women and 13 men. CEAP class was C2EpAsPr, describing varicose veins, primary etiology, and saphenous reflux. UGFS followed thermal ablation of the great saphenous vein. Foam was prepared using the three-way tap technique to mix gas with 1% polidocanol in a 4:1 ratio. Segments of the great and small saphenous veins and their tributaries were treated with UGFS. Foam volumes injected were (SD) (6-46 range) and (6-57 range) ml for air- and CO 2 -based foams respectively P (.39). Incidence of adverse events was compared by 2 statistics. Vital signs were compared by paired t test. Results: During the procedure, the average heart rate decreased by less than 5 bpm for both groups P <.001), ( and blood pressure decreased by less than 3 mm Hg in the 2 group CO (P <.02). Respiratory rate, electrocardiogram, and pulse oxymetry did not change significantly in both air- and 2-foam CO series (P >.05). Visual disturbances were experienced by 3.1% (4/128) and 8.2% (4/49) patients in the 2 CO and air groups respectively P (.15). Respiratory difficulties or circumoral paresthesia each occurred in 0.8% (n 1) of the CO 2 patients. Incidence of chest tightness (3.1% vs 18%), dry cough (1.6% vs 16%), or dizziness (3.1% vs 12%) were significantly lower in the 2 vs CO air groups P ( <.02). Nausea occurred in 2% and 4% of the 2 CO and air-based foam groups P (.53). Overall, the proportion of patients describing side effects decreased from 39% (19/49) to 11% (14/128) as 2 replaced CO air for foam preparation P ( <.001). Similar findings were described in the literature of air-based foam but data on the use of physiological gas were rare. Conclusions: Side effects decreased significantly if CO 2 rather than air was employed to make the sclerosing foam for chemical ablation of superficial veins of the lower extremity. ( J Vasc Surg 2008;47:830-6.) Endovenous chemical ablation, ultrasound-guided therapy has been used to successfully treat: (1) saphenous foam sclerotherapy (UGFS) in particular, has become a veins primarily, (2) to complement, complete, or extend common treatment of patients with chronic venous valvular stripping or thermal ablation by laser or radiofrequency, (3) insufficiency. 1,2 The foam is produced by agitating a gas withrecurrent veins, (4) venous malformations, (5) venous an- (6) sciatic nerve varices, and (7) saphenous or a detergent, liquid sclerosant. Air has been commonly em-eurysmsployed but a more physiological gas such as carbon dioxidenonsaphenous perforating veins. 1-7 (CO 2 ) may have certain advantages. Foam can be prepared 2,8 in a variety of ways to treat small or large veins, improves ultrasound (US) visualization of the venous lumen, more i s Side effects and adverse events have been described not only for UGFS but for all methods of treating the superficial veins of the lower extremity, surgical or nonsurgi The gas in the foam may have the potential for local, effective than liquid at lower dosages of sclerosant, and hascal. become an efficient alternative to venous phlebectomy or pulmonary, visual and/or cerebral effects, particularly in a stripping. 4,6,7,9-16 patient with a patent foramen ovale or other, right-to-left Patients of all abnormal, clinical, CEAP classes have shunt. W e have tracked foam, or gas bubbles, to the right 1,2,4,6,7,11-14,16-28 been treated with UGFS. Foam sclero- and left chambers of the heart and to the middle cerebral artery using transcutaneous, transthoracic echo (TTE), 36 and transcranial Doppler (TCD). In the initial phase of our experience, the safety profile of air-based polidocanol foam was evaluated in-house. Contemplating the use From the Morrison Vein Institute a and Compudiagnostics, Inc. b Competition of interest: Dr Morrison has received fees for consulting from of a more physiological gas, CO 2, an investigation was Provensis (sponsors of the work described in reference 7). The present study was sponsored by the authors. repeated for CO 2 -based foam. Therefore, this cohort Reprint requests: Nick Morrison, MD, Morrison Vein Institute, 8575 East Princess Dr Suite 223, Scottsdale, AZ ( nickmorrison@ study, with comparison with historical control, focused on two primary objectives: (1) to evaluate possible toxicity and complications of CO 2 -based foam; and (2) to morrisonveininstitute.com) /$34.00 Copyright 2008 by The Society for Vascular Surgery. compare the safety profiles obtained for CO 2 vs air as two doi: /j.jvs distinct gases used in UGFS. 830

2 JOURNAL OF VASCULAR SURGERY Volume 47, Number 4 Morrison et al 831 PATIENTS AND METHODS A prospective study was designed to investigate the incidence of side effects and adverse reactions of a carbon dioxide (CO 2 )-based foam for chemical ablation in the treatment of chronic venous valvular insufficiency. The results were compared with a similar prospective investigation previously performed to evaluate air-based foam. Patient population. Subjects who were candidates for chemical ablation received instructions about polidocanol, its use in Europe, Canada, and the United States, its status with the Federal and Drug Administration (FDA), and potential alternative treatments. Patients signed informed consents for treatment with polidocanol and for participation in the quality assurance research program. Subjects entered either study after thermal ablation of the great saphenous vein (GSV). Thermal ablation was performed either with laser or radio-frequency. The GSV was occluded to the saphenofemoral junction (SFJ). Concurrent ambulatory phlebectomy was performed as indicated for the treatment of varicose veins. Tributaries of the SFJ were not treated. Other abnormal, superficial veins remained patent after the initial GSV ablation. The thermal ablation procedure was followed by chemical ablation at one-week to eliminate (1) the GSV distal to the ablated segment, (2) saphenous tributaries, (3) a refluxing small saphenous vein, (4) other superficial veins with reflux or with potential to be part of a refluxing network, and/or (5) some unablated or recanalized segment of the GSV previously treated. Investigations of air- and CO 2 -based foams included 49 and 128 patients: 44 women and 5 men and 115 women and 13 men, respectively. Predominance of female gender had a 9:1 ratio. The subjects evaluated represented common patients seen in a phlebology outpatient clinic of a thriving urban community. Young adults to active retired people were treated. Average age of the air-based foam group was (SD), ranging from 23 to 80 years. Average age of the CO 2 -based foam group was (SD), ranging from 29 to 89 years. The CEAP classification of both groups was C2EpAsPr describing varicose veins, primary etiology, and saphenous anatomy with reflux lasting longer than 500 msec. Foam preparation. A liquid sclerosant, polidocanol, was mixed with gas in a 4:1 gas/liquid ratio. Liquid polidocanol was diluted to 1%. In the initial safety profile study, the gas employed was air. In this update, carbon dioxide (CO 2 ) was mixed with liquid polidocanol. The three-way tap technique described by Tessari was employed to prepare the foam. 17 Foam injection. Foam was injected under ultrasoundguidance. The first injection was performed distally. Foam progression was followed by ultrasound to determine the site of the following injection. Injections were stopped once foam approached a connection to the deep venous system. Foam volumes. The average volume of air-based foam injected was (SD) ml, ranging from 6 to 46 ml. The average volume of CO 2 -based foam injected was (SD) ml, ranging from 6 to 57 ml. The end point of treatment was the perceived injection of foam by ultrasound in the various venous segments selected for treatment. Total volume injected became a theoretical endpoint since the volumes injected in these studies exceeded the maximum volumes described by other investigators. 11 Patient monitoring. A registered nurse (RN) monitored vital signs at various times: (1) preinjection; (2) every 15 minutes during the injection procedure; and (3) 30 and 60 minutes after the procedure was terminated. The following vital signs were monitored: systolic and diastolic blood pressures, heart rate, respiratory rate, electrocardiogram (ECG), and pulse oximetry. The RN also monitored and registered sequelae, side effects, complications and/or patients statements of unusual sensations every 15 minutes during the procedure and ½, 1, 2, 4-6, and 24 hours after the procedure. The expected sequelae were: (1) injection site itching; and (2) localized leg pain. Side effects or complications specifically monitored for were: (1) chest tightness; (2) dry cough; (3) metallic/medicinal taste; (4) nausea; (5) dizziness; (6) circumoral paresthesia, (7) respiratory difficulty; and (8) visual disturbance. All nurses involved with the study had up to 10 years of extensive experience dealing with patients being treated for chronic venous insufficiency in an outpatient setting. A patient-supporting role was an intrinsic part of their participation. Besides being available to counsel the patients and address their questions and concerns about the treatment being performed, the nurses were instructed to ask the patients to describe their condition at set intervals; they did not volunteer an answer or ask specific questions about the items mentioned above. Suggestions were avoided but, in contrast, the patients had freedom to express their concerns and unusual sensations. The phrases used by the patients were then recorded and compared with the closest item in the list. For example, aching was classified as leg pain. The 2-hour, 4-6-hour, and 24-hour interviews were conducted by phone. Although not blind to the gas used, the RNs in the clinic had no apparent reason to favor one type of gas over another. Patients wore loose clothing, slacks, or shorts and brought two pairs of support hose to the injection sessions. Patients were asked not to shave or apply lotion to their legs the morning before the injections. Emphasis was placed on postinjection compression. The patients were instructed to wear two pairs of compression hose during the day for the first 48 hours and to sleep with one pair only for those two nights. Shower was allowed but hose had to be reapplied promptly. Patients had to take, at a minimum, a brisk 30-minute walk every day in their support hose. Normal activities were resumed immediately after injection with the support hose in place. Strenuous activity had to be avoided for 2 days. Weight lifting had to be avoided for 2 weeks, and hot baths, hot showers, saunas, steam rooms, and whirlpool type tubs for 2 to 3 weeks. Prescribed baby aspirin were taken and patients could take acetaminophen for pain or discomfort. A list of anti-inflammatory medicines not to be

3 832 Morrison et al JOURNAL OF VASCULAR SURGERY April 2008 Table I. Vital signs associated with chemical ablation Ultrasound-guided foam sclerotherapy Liquid: 1% polidocanol Gas: air or carbon dioxide (CO 2 ) Preprocedure 15 min into procedure 60 min postprocedure Air-based foam Heart rate (bpm) (SD) Respiratory rate (rpm) PO2 (%) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) CO 2 -based foam Heart rate (bpm) Respiratory rate (rpm) PO2 (%) Systolic pressure (mm Hg) Diastolic pressure (mm Hg) taken for 1 week was provided to the patients. Iron or vitamin E supplements were to be avoided for 2 days before and 2 weeks after injections. The patient spent most of the first hour after treatment getting ready with support hose, dressings, and performing mild activity in the clinic while receiving detailed instructions. This basic protocol was similar to all patients in the air- and CO 2 -based foam groups. Statistical analysis. Vital signs comparisons were performed using the paired t test provided with the Excel program (Microsoft, Inc, Seattle, Wash). Incidence of side effects and adverse events observed for the air- or CO 2- based foam groups were compared using the 2 program also provided with the Excel program. Table II. Side effects following chemical ablation Condition Ultrasound-guided foam sclerotherapy Liquid: 1% polidocanol Gas: air or carbon dioxide (CO 2 ) Gas Air CO 2 Chest tightness 9 (18%) 4 (3.1%) P.001 Dry cough 8 (16%) 2 (1.6%) P.001 Dizziness 6 (12%) 4 (3.1%) P.019 Visual disturbance 4 (8.2%) 4 (3.1%) P.15 Metallic/medicine taste 0 (0%) 2 (1.6%) P.39 Nausea 2 (4%) 3 (2%) P.53 Circumoral paresthesia 0 (0%) 1 (0.8%) P.53 Respiratory difficulty 0 (0%) 1 (0.8%) P.53 Total 49 (100%) 128 (100%) RESULTS After injection of air- or CO 2 -based foam, there were no physiologically significant changes in vital signs or in the electrocardiogram (Table I). However, statistically significant differences were noted in the following vital signs measured at base line and during foam injection: (1) during air-based injection, the average decrease of 4 bpm in heart rate was significant (P.001 by paired t test); and (2) during CO2-based injection, the average decreases of 3 bpm in heart rate (P.001), 4 mm Hg in systolic blood pressure (P.001), and 2 mm Hg in diastolic blood pressure (P.03) were significant by paired t test. Localized itching was reported by 6% (3/49) and by 15% (19/128) of the patients receiving air- or CO 2 -based foam injections, respectively (P.12). Localized pain was reported by 22% (11/49) and by 20% (26/128) of the patients in the air- and CO 2 -based foam groups, respectively (P.75). Table II presents the incidence of side effects and complications following air- or CO 2 -based foam sclerotherapy. Chest tightness, dry cough, and dizziness decreased significantly by substituting CO 2 for air as a gas to form the sclerosing foam. Average air-based foam volumes injected in patients reporting vs patients not reporting (1) chest tightness, (SD) vs ml, (2) dizziness, vs ml, or (3) leg pain, vs ml, were not statistically significantly different (P.37). A statistically significant higher volume was injected in patients reporting vs not reporting dry cough, 35 9vs24 9mL (P.005). No side effects or complications listed in Table II were reported by five patients receiving less than 15 ml of air-based foam. The four patients reporting visual disturbances received 27, 17, 15, and 15 ml of air-based foam. Average CO 2 -based foam volumes injected in patients reporting vs patients not reporting (1) events listed in Table II, (SD) vs ml, or (2) leg pain, 23 9 (SD) vs ml, were not statistically significantly different (P.36). The four patients reporting visual disturbances received 8, 16, 18, and 40 ml of CO 2 -based foam. The figure reports and compares the probability of occurrence of chest tightness, dry cough, and/or visual 2

4 JOURNAL OF VASCULAR SURGERY Volume 47, Number 4 Morrison et al 833 Fig. Endovenous chemical ablation: event probability as a function of air- or carbon dioxide (CO 2 )-based foam sclerotherapy with volumes less than indicated in the horizontal axis. disturbance for air- and CO 2 -based foam. These events did not occur if the volume of foam injected was less than ml. Above these values, the event probability was not related to volume injected. In these studies, however, only five (10%) and 15 (12%) patients in the air- and CO 2 -based groups had such low volumes injected. A 30% to 40% incidence of such events with air-based foam decreased to less than 10% if CO 2 were used rather than air. In summary, 39% (19/49) and 11% (14/128) of the patients in the air- and CO 2 -based foam groups, respectively, reported events listed in Table II (P.001). With the exception of one patient in the CO 2 group reporting nausea, all these events cleared within 24 hours. DISCUSSION The evolution from visual liquid sclerotherapy to (1) ultrasound-guided liquid sclerotherapy, (2) air-based foam, and, presently, (3) a more physiological gas, eg, CO 2- based foam has growing evidence presented in the literature. The safety profile studies performed in our own clinic also favored the use of a physiologic gas, CO 2, to create the foam needed for chemical ablation of insufficient superficial veins of the lower extremity. In our practice, transitions occurring in chemical ablation have been monitored clinically, physiologically, and ultrasonographically. The nurses involved in the recording of events had several years of experience in dealing with patients being treated in an outpatient phlebology clinic. Of interest in the methodology employed, the patients did not receive suggestions of signs, or symptoms being investigated. Any description of side effects had to be volunteered by the patient. Some events, specifically dry cough, were observed directly while the patients were still in the clinic. Transthoracic echo (TTE) and transcranial Doppler (TCD) have been employed to demonstrate if a foramen ovale is patent and if bubbles can reach the brain. 36 This study with CO 2 -based foam, as well as its predecessor with air-based foam, was designed to record the patients vital signs, side effects, and adverse reactions following a prospective, monitored protocol. The incorporation of foam sclerotherapy was based on reports describing a broad international experience. Feasibility, effectiveness, efficacy 4,6,17-19,21,23-29,31,34,37-39 and comparative 5,7,10,12-16,20,22,40-41 studies have been conducted in many countries and distinct continents. The transition from air to a physiologic gas has been supported by the experience of Cabrera in Spain and by the international trials conducted by Provensis to test the physiologic mix Varisolve. 3-7,18,23,29 In particular, Cabrera et al have injected larger amounts of physiological foam than those recommended by consensus based primarily on air-based foams. 11 This study and our general experience are in accordance with the injection of large volumes of foam. The events described were not directly related to the volume of foam used. Only dry cough with air-based foam had a relation to foam dosage. Side effects, adverse reactions, and minor or major complications following foam sclerotherapy have been limited in incidence and in duration. Different objectives, varying descriptions, and low incidence make it difficult to analyze the information presented in the literature. Most published reports described experiences with air-based foam. The following is a summary of observations similar to the ones described in this work relating adverse events. Adverse events: air-based foam. Visual disturbances or scotomas have been a major focus of attention when evaluating adverse events following foam sclerotherapy. Frequencies of occurrence, as mentioned in the literature, varied from 0% to 6% following air-based foam injection ,19,21-22,24,26,34,37-38 Most publications indicated a frequency of less than 1%. Our prospective evaluation showed frequencies of occurrence of 8% for air- and 3% for CO 2 -based foams. The prospective nature of this study may have resulted in slightly higher findings. Respiratory difficulties were not reported by our patients in the air-based foam series, with only one patient having such problems after CO 2 -based foam injection. Pulmonary embolism is a concern, but its occurrence is rare and may relate more to other patient conditions than to the procedure itself. Pascarella et al reported one case of pulmonary embolism occurring 4 months after the procedure. 25 Forlee et al reported one case of stroke following varicose vein foam injection sclerotherapy. 35 The patient had an undiagnosed, very large, patent foramen ovale. The opinion of international experts was that this single episode should not justify presclerotherapy clearance for patent foramen ovale or right-to-left shunts. 42 Thousands of patients with patent foramen ovale have been treated with foam sclerotherapy without adverse events. 34 Serious incidents may occur not only after foam sclerotherapy but also after liquid sclerotherapy or surgical stripping as attested by the reports on cardiac arrest and brain infarct. 32,33 The practicing phlebologist should have protocols to deal with such a serious adverse event if one occurs. Other events included in this investigation have been rarely reported. A prospective study like ours, focusing on

5 834 Morrison et al JOURNAL OF VASCULAR SURGERY April 2008 such events, may have frequencies higher than retrospective evaluations. The following are some comments about the events listed in Table I. Chest thightness was mentioned by Bergan et al as an adverse event; only a few of their patients described this condition. 26 In our studies, chest thightness occurred with a significant frequency when air-based foam was used, 18%, and decreased significantly to 3% when CO 2 -based foam was administered. Dry cough was also mentioned by Bergan et al as an adverse event that occurred infrequently. 26 Our study also had a higher frequency with air-based foam, 16%, decreasing to less than 2% with CO 2 -based foam. Dizziness apparently has not been formally reported or investigated in a prospective manner. Alos et al indicated that none of their patients had dizziness. 15 We found a significant frequency of 12% with air-based foam that decreased to 3% with CO 2 -based foam. Nausea also has not been formally reported after a prospective evaluation. In our studies, the frequency of nausea was relatively small and the decrease with the change in gas was not statistically significant. Metalic or medicinal taste has not been formally evaluated or described. This event occurred twice after CO 2 - based foam injection, and, perhaps, should not influence daily practice. Paresthesia was also mentioned by Bergan et al as occurring infrequently. 26 In our evaluation, no patient reported paresthesia. Minimizing this event seems to be a major advantage of foam-based chemical ablation when compared with surgical stripping. Other events have been described in the literature. True migraine or occular migraine was experienced by a couple of patients as described by Bergan et al. 26 Transient confusion had a frequency of about 1% according to Frullini et al. 19 Neurasthenia has been reported but with an insignificant frequency. 21,24 The frequencies of occurrence of tissue necrosis have been reported as less than 2%. 19,26,31 Tissue necrosis can be insignificant in general, but it can have a significant incidence when varicose vein patients are excluded from the calculation Tissue necrosis occurred in about 1% of patients with skin changes and ulcers (CEAP clinical classification C4 to C6), perhaps between 1% and 10% for a small group of patients with open ulcers, or in close to 17% (1/6) in patients with angiomata. The later statistics are affected by the small number of cases but raise the concept that adverse event frequencies are dependent on the conditions of the patients. Improved care must take into consideration the frequency of events in very specific populations. Venous thrombosis has been reported as expected. This adverse event can be separated in four major groups: (1) extensive deep venous thrombosis involving the femoropopliteal veins; (2) thrombus extension into a small segment of the common femoral or popliteal vein; (3) deep venous thrombosis limited to calf veins; and (4) superficial thrombophlebitis. Extensive femoropopliteal thrombosis following chemical ablation has been rare. A preprocedure clinical history for familial and individual, hypercoagulable states, most likely, can minimize occurrences of this event. 2 Extension of thrombosis to the femoral or popliteal veins has been described by several authors with an incidence of less than 2%. 16,19,37-39 Calf thrombosis limited to the posterior tibial or gastrocnemius veins has also been described with an incidence varying from near 0% to 4%. 16,21,24-26,38 Such frequencies may also be dependent on the overall condition of the patient and may be lower for patients with simple varicose veins compared with patients with advanced chronic venous insufficiency. Superficial thrombophlebitis, in principle, should be considered a direct consequence of the treatment. This finding, however, is considered an adverse event if thrombophlebitis extends beyond the region treated or if the inflammation is significantly worse than commonly expected. Therefore, one should expect the reports to be highly variable and subject to individual interpretation. Incidences have been reported varying from 1% to 11%, or even 33% for a specific population with reflux starting in the veins at the groin. 14,17,19,31,37-38 Significant inflammation has occurred with an incidence close to 5%. 10,21,24 Hamel-Desnos described the incidence of hematomas at about 2%. 10 Frequency of telangiectatic matting was insignificant according to Barrett et al. 21,24 Adverse events CO 2 -based foam. CO 2 has not been used as much as air and the literature on adverse events reflects such a pattern. The experience of Cabrera s group and findings of the Provensis international research are summarized below. Transient visual disturbances and dry cough were described by two patients each for an incidence of less than 2%. 23 This report indicates usage of 20 to 30 ml of foam to treat the saphenous vein. The mixed gas used was primarily CO 2 and O 2. Coughing, inflammation, and photopsia were reported in Treatment of venous malformations was performed with volumes up to 80 ml. 29 Skin necrosis was an adverse event in 6% of the patients. An injection in a small arterial branch was reported. Deep venous thrombosis, pulmonary embolism, or neurological symptoms did not occur as mentioned in the 2000, 2001, and 2003 reports. 4,18,29 Apparently CO 2 -based foam does not increase the risk of deep venous thrombosis. Anecdotal descriptions of thrombosis in calf veins near treatment sites have been mentioned. Superficial thrombosis has also been reported. The incidence of significant superficial thrombophlebitis was 10%. 23 The Varisolve report of 2006 described mild contusion, skin discoloration and limb pain. 7 A very small proportion of transient paresthesias, or visual and speech disorders occurred with Varisolve. Cardiopulmonary adverse events suggestive of gas embolism did not occur. Incidence of headache was similar for the Varisolve vs saphenous stripping comparison, or for the Varisolve vs other sclerotherapy comparison. In total, however, the frequency of headaches

6 JOURNAL OF VASCULAR SURGERY Volume 47, Number 4 Morrison et al 835 was highest after surgery. Deep venous thrombosis occurred in 4.5% of the Varisolve patients in the surgery comparison group and 0.8% in the sclerotherapy comparison group. This adverse event did not occur after changes in protocol requiring less volume and compression when foam approached the saphenofemoral or popliteal junctions. In summary, this cohort study evaluated a physiological gas alternative for endovenous chemical ablation. Comparison with historical control was performed in a stable clinical population treated with similar volumes of foam for similar varicose vein problems. Heart rate, respiratory rate, electrocardiogram, and pulse oximetry were not physiologically affected by UGFS. This report confirmed the low incidence of visual disturbances and respiratory distress that may occur after UGFS. It documented a significant decrease in chest thightness, dry cough, and dizziness when carbon dioxide replaced air. For volumes greater than 15 ml, incidence of complications or side effects were not directly related to volume of foam injected; compared with air, use of CO 2 resulted in a three-to fourfold decrease in chest tightness, dry cough, and/or visual disturbance. Use of a physiological gas can minimize short-term side effects associated with foam sclerotherapy of superficial veins of the lower extremity. The authors thank Kathy Melfy, RN, BSN, Christine Hall, RN, BSN, Pam Norris RN, BSN, Sharon Olbert, RN, BSN, Barbara Deusterman, RN, BSN, Ellen Allen, RN, Janice Moreno, RN, BSN, CVN, Shannon Levin, RVT, and Kristin Hansen, RVT, RDCS. AUTHOR CONTRIBUTIONS Conception and design: NM, CR, JM, EJ, DN, TM, SS-C Analysis and interpretation: NM, EJ, SS-C Data collection: NM, DN, CR, JM, EJ, TM Writing the article: SS-C Critical revision of the article: NM Final approval of the article: SS-C, NM Statistical analysis: SS-C (initially, a statistician was consulted) Obtained funding: NM, TM, CR, JM, DN Overall responsibility: SS-C, NM REFERENCES 1. Bergan JJ, editor. The vein book. Burlington, MA: Elsevier Academic Press; Goldman MP, Bergan JJ, Guex JJ, Partsch H, Ramelet AA. Sclerotherapy: Treatment of varicose and telangiectatic leg veins. 4 th ed. Philadelphia, PA: Mosby-Elsevier; Cabrera J, Cabrera J Jr. Nuevo método de esclerosis en las varices tronculares. Patologia Vasculares 1995;4: Cabrera J, Cabrera J Jr, Garcia-Olmedo MA. Treatment of varicose long saphenous veins with sclerosant in microfoam form: long-term outcomes. Phlebology 2000;15: Eckmann DM, Kobayashi S, Li M. 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